Pain is the most common symptom for which patients seek medical assistance. In the case of incurable diseases, treatment for pain may last for extended periods of time. Pain is both a physical and an emotional experience which differs greatly from one individual to another. Although subjective, most pain is associated with tissue damage and has a physiological basis.
Pain can be either acute or chronic. Acute pain is generally caused by sudden injury, tissue damage, or infection for which the cause is easily found. Chronic pain, however, is the pain of pathological conditions and often difficult to isolate and treat. Chronic pain is routinely defined as pain of over six months duration.
For patients suffering from chronic pain, the autonomic nervous system adapts to the pain and evidences of autonomic hyperactivity such as tachycardia, hypertension, diaphoresis, mydriasis, and pallor disappear, leaving the physician to rely on the patient's subjective complaints in assessing chronic pain.
In the management of chronic pain, some types of pain permit treatment of the underlying disorder, i.e., radiation treatment for pain caused by bone cancer. In some cases, a particular treatment is given for a specific type of pain, i.e., treatment of trigeminal neuralgia or glossopharyngeal neuralgia with carbamazepine, reflex sympathetic dystrophies with local anesthetic, postherpetic neuralgia with direct stimulation.
In many patients, however, the pain is chronic and the physician can neither treat the underlying disturbance nor prescribe a specific therapy for that type of pain. For example, osteoarthritis is a joint disease characterized by degeneration and loss of articular cartilage and by osteophyte formation, or bony outgrowth of subchondral bone. The disease is slowly progressive, leading to chronic pain and stiffness and gradually to increasing dysfunction of the affected joint. The incidence of the disease increases with age and affects three times as many women as men.
Chronic joint pain, swelling, creaking, and stiffness are the most prominent symptoms of osteoarthritis. The disease commonly affects the distal interphalangeal joints of the hands, resulting in bone enlargements often accompanied by inflammation and pain. Weight bearing joints such as the neck, lower back, knees and hips are often affected by this type of arthritis.
Another major symptom of osteoarthritis is loss of articulation of the joint. Weakness and shrinkage of surrounding muscles may occur if pain prevents the joint from being used regularly. As movement of an affected joint becomes severely limited, the sufferer experiences loss of functionality of the joint. In the case of osteoarthritis of the hip or knees, ambulation becomes impaired.
Although osteoarthritis is the most common of the rheumatic diseases, its pathogenesis is not well understood, and currently there is no treatment that will retard or reverse pathological processes in the disease. The only treatment available to osteoarthritis sufferers has involved symptomatic treatment through analgesics for pain and nonsteroidal anti-inflammatory agents for reduction of joint inflammation. An injection of a corticosteroid may also be administered to a painful joint.
Chronic pain is also associated with multiple sclerosis (MS), also known as disseminated or insular sclerosis, a disease of the central nervous system (CNS) characterized by widespread patches of demyelination in the brain and spinal cord. The disease occurs worldwide in about 10-60 persons per 100,000 with the age at onset occurring at about 20-40 years, and appears to affect females more often than males. While MS is generally chronic and relapsing, fulminating attacks occur, and as many as 30% of the patients progress steadily from the onset.
Although multiple sclerosis is the most common demyelinating disease, its cause is unknown, and there is no treatment to retard or reverse the pathological processes of the disease. There is no specific therapy recommended because spontaneous remissions make treatment difficult to evaluate. The only treatment available to multiple sclerosis patients include corticosteroid therapy (e.g., prednisone or dexamethasone) until manifestations remit, and symptomatic treatment such as baclofen for spasticity and pain relievers such as analgesics and opiates.
There are several types of drugs used to decrease chronic pain. Analgesics are drugs used to decrease pain without causing loss of consciousness or sensory perception. There are two basic classes of analgesics: anti-inflammatory, routinely prescribed for short-term pain relief and for modest pain, and opioids used for either short-term or long term pain relief of severe pain. The anti-inflammatory analgesics generally provide analgesia, anti-inflammation, and antipyretic action. It has been reported that the mechanism of action may be to provide inhibition of the synthesis of prostaglandins. W. W. Douglas, "Polypeptides--angiotensin, plasma kinins, and other vasoactive agents; prostaglandins," The Pharmacological Basis of Therapeutics, 9th edition, L. S. Goodman and A. Gilman (eds.), MacMillan Publishing Co., Inc., New York, 1975. Prolonged use of anti-inflammatory analgesics have been known to cause gastrointestinal problems.
The opioid analgesics, or narcotics, include all natural or synthetic chemical compounds closely related to morphine and are thought to activate one or more receptors on brain neurons. Opioid analgesics have serious side effects and thus are used with discrimination. These side effects include: 1) tolerance, which requires gradually increasing doses to maintain analgesia; 2) physical dependence, which means that the narcotics must be withdrawn gradually if they are discontinued after prolonged use; 3) constipation, which requires careful attention to bowel function, including use of stool softeners, laxatives, and enemas; and 4) various degrees of somnolence, or drowsiness, which requires adjustments in dosages and dose scheduling, or possibly varying the type of narcotic to find one better tolerated by the patient.
It has been reported that various treatments for pain are additive and should be used together rather than separately. For example, the combination of aspirin or acetaminophen and codeine is often prescribed to provide pain relief stronger than codeine by itself. Certain antidepressants prescribed for depression have been recommended as an analgesic adjuvant.
While pain management has been a problem faced by physicians for many years, available pain medications have ameliorated, but not alleviated the problem of pain treatment. A significant problem remains in that detrimental side effects are often caused by pain-relieving medications as detailed above. Thus, there remains a continuing need for alternative pain therapy regimens which would address the need for pain reduction but also reduce these side effects.
Surprisingly, it has now been discovered that N-L-.alpha.-aspartyl-L-phenylalanine 1-methyl ester and derivatives have analgesic properties, relieving pain and restoring function of soft tissues, muscles, ligaments, tendons, bones, and joints. Further, when taken in combination with other analgesic agents, N-L-.alpha.-aspartyl-L-phenylalanine 1-methyl ester provides an additive analgesic effect. The detrimental side effects inherent in pain therapy known to the art can be reduced through the use of N-L-.alpha.-aspartyl-L-phenylalanine 1-methyl ester in pain therapy and management.